Failure of remission induction by glucocorticoids alone or in combination with immunosuppressive agents in IgG4-related disease: a prospective study of 215 patients

IgG4-related disease (IgG4-RD) is an immune-mediated systemic fibro-inflammatory disease, which is characterized by enlargement of the involved organs, elevated serum concentrations of IgG4, and pathology findings of dense lymphoplasmacytic infiltration enriched in IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis and mild-to-moderate eosinophilia [1‐4].

Glucocorticoid (GC) is the standard first-line agent for remission induction [5]. Patients with IgG4-RD typically respond well to initial GC treatment, with improvement of symptoms and signs, resolution of enlarged organs and decrease in serum IgG4 levels [6‐10]. In addition, combination therapy comprising GC and immunosuppressive agents (IM) has also been shown effective, while the necessity of combination therapy from the beginning of treatment remains controversial [11‐16].

Of note, there is a small minority of patients with less favorable response to remission induction, including those who have persistently active disease despite treatment, relapse during GC tapering or fail of GC tapering because of unstable disease [12, 17‐20]. However, there are limited data on patients with less favorable response.

Here, we assessed the outcomes of remission induction  in 215 patients with IgG4-RD in our prospective cohort, who were treated with GC alone or in combination with IM, and investigated the characteristics, prognosis, and risk factors among patients who failed of remission induction.

In this article, we assessed the outcome of remission induction in 215 patients with IgG4-RD, who were treated with GC alone or in combination with IM, and focused on the subpopulation of patients with less favorable response to treatment.

Treat-to-target approaches, in which treatment regimens are escalated or adjusted until a specific target is reached, have been applied as routine management of patients with a variety of chronic diseases, and have been demonstrated to improve treatment outcomes significantly [24‐28]. However, the therapeutic goals in IgG4-RD have not been clearly defined. It has been reported that in patients with IgG4-RD, persistently active disease could lead to fibrosis and irreversible organ damage [1, 2, 29]. Therefore, early intervention is critical, and it is also important to clarify the therapeutic goals of remission induction and confirm that the patients are receiving adequate treatment. Here, based on our experience, we defined the therapeutic goals of remission induction as fulfilling each of the following after 6-month treatment: (1) ≥ 50% decline in the IgG4-RD RI; (2) GC tapered to maintenance dose (prednisone ≤ 10 mg/day); and (3) no relapse during GC tapering (within 6 months). The patients not fulfilling the treatment goals were considered as failure of remission induction. We are aware of the possibility that the serum IgG4 level might not be lowered even if the treatment was effective, resulting in unsatisfactory decline in the IgG4-RD RI, and therefore some patients even in clinical remission might be classified as remission induction failure. However, in our cohort, only three patients failed of remission induction based on this criterion, and all three presented with persistently active disease in the affected organs, accompanied by failure of GC tapering to maintenance dose. Further validation is required for the treatment goals proposed by us.

Most of the patients reached remission through 6-month treatment, while 26 patients (12.1%) failed of remission induction (16 (20.8%) with GC monotherapy, and 10 (7.2%) with combination therapy comprising GC and IM). The baseline features were almost comparable between the two groups (Table 2), while the incidence of remission induction failure in the patients treated with GC monotherapy was significantly higher (p = 0.008). On the other hand, the patients treated with combination therapy did not experience more side effects compared to those treated with GC monotherapy (Additional file 2). It remains controversial whether some patients require the combination of GC and IM from the beginning of treatment [5]. Our data, along with previously published data showing that the patients treated with GC + CTX had a significantly higher rate of complete remission and lower rate of relapse [11], support the necessity of combination therapy with GC and IM as the initial treatment in certain patients.

Failure of remission induction most commonly occurred in the lacrimal glands and lungs (Fig. 3a). In the patients treated with GC monotherapy, lungs, lacrimal glands and bile duct had the highest incidence of remission induction failure (29.4%, 25.7% and 13.6%, respectively), indicating that the patients with involvement of these organs need more intensive follow up (Fig. 3b). In the patients treated with a combination of GC and IM, the overall incidence of remission induction failure was low, with relatively higher incidence in the pancreas and lacrimal glands (Fig. 3b).

Among the 23 patients who relapsed during GC tapering, re-treatment either with more intensive GC therapy or with the addition of or change in IM was effective in most of the patients (17/21, 81.0%), which is consistent with data from other studies [6, 12, 30]. Of note, among the patients who relapsed, secondary relapse occurred in 52.9%, which is much higher than the overall relapse rate with initial therapy (21.4%), indicating that the patients who have relapsed are susceptible to another relapse, and they need more intensive follow up.

Of note, there are four patients in our cohort (patient number 3, 15, 16 and 24) (Additional files 3 and 4), who had persistently active disease refractory to multiple treatment regimens. Although unresponsiveness to various treatment regimens is rare in IgG4-RD, diagnosis of IgG4-RD in those patients was confirmed by biopsy, and conditions that could mimic IgG4-RD, including anti-neutrophil-cytoplasmic antibody (ANCA)-associated vasculitis, multicentric Castleman’s disease, Kimura disease, Rosai-Dorfman disease and cancer, etc., were excluded. In accordance with our data, Wallace et al. reported three patients with IgG4-RD unresponsive to treatment with GC and/or rituximab [18]. Sun et al. reported three cases of IgG4-related lung disease, that were either unresponsive to a routine dose of GC, or failed GC tapering because of recurrent disease [20]. Taken together, it is possible that a small minority of patients with IgG4-RD is refractory to treatment, and further study on the management of those patients is required.

In the patients treated with GC monotherapy, eosinophilia, higher baseline RI, more than five organs involved and dacryoadenitis were identified as risk factors for remission induction failure (Table 3). Consistent with our data, it has been reported that higher baseline RI and greater number of organs involved are associated with worse outcomes with GC therapy [11, 19]. Eosinophilia is a common clinical manifestation in patients with IgG4-RD [3, 4]. Interestingly, it has been proposed that eosinophilia is associated with the inherent characteristics of IgG4-RD, rather than underlying allergy [31]. Our previous study also demonstrated that peripheral eosinophils was associated with disease severity, indicated by the number of organs involved and serum IgG4 levels [32]. Here, we also found that eosinophilia, rather than allergy history, is associated with treatment outcome. The etiology of eosinophilia in patients with IgG4-RD and its role in pathogenesis requires further investigation. As for particular organ involvement, dacryoadenitis is a newly discovered risk factor for worse outcome. In contrast to our study, it has been reported that in the patients with autoimmune pancreatitis, the presence of sclerosing cholangitis is a risk factor for relapse [6]. The discrepancy could be caused by the difference in disease subtypes and observation endpoints (failure of remission induction vs relapse).

When the patients treated with GC monotherapy were grouped according to the number of risk factors at baseline, we identified a trend towards higher incidence of remission induction failure in the patients with more risk factors (Fig. 3c). Of note, in the patients with more than three risk factors, the incidence of remission induction failure was as high as 71.4%. As aforementioned, remission induction failure was more common in the patients treated with GC monotherapy. Taken together, our data suggest the necessity of combination therapy with GC and IM for the patients with more than three risk factors.

In addition, after the remission-induction stage, serum ESR, CRP and IgG4 was significantly higher in the patients who failed of remission induction (Fig. 4), indicating the usefulness of these serological parameters to assess response to treatment. Consistent with our data, it has been reported that in patients with autoimmune pancreatitis, persistent elevation of IgG4 level after treatment is associated with persistent abnormalities of the pancreas and bile duct and more frequent relapse [7]. It has been proposed that the quantitation of circulating plasmablasts is better for monitoring disease activity than IgG4 level [18, 33]. However, considering the clinical availability, it is still valid to monitor serum IgG4 during follow up.

Our study also has some limitations. The biopsy-proven diagnosis rate was 52.1%, and the remaining patients were diagnosed based on clinical manifestation and serum IgG4 levels. However, all the patients without biopsy-proven diagnosis presented with typical features of IgG4-RD, conditions that could mimic IgG4-RD were excluded and the treatment outcomes were comparable in the patients with different diagnostic status (Additional file 1). In addition, the therapy regimens are varied between patients, including the initial doses of GC, the duration of initial dose and the type of IM. However, in logistic regression analysis there was no association between the risk of remission induction failure and either the initial GC dose or duration of the initial dose (Table 3). In addition, previous research from our group found no significant difference in the efficacy of high and medium doses of GC in the induction of remission [34]. We infer that the difference in GC dose and tapering did not cause much bias. On the other hand, the differences in usage of IM might be the reason why no risk factors for remission induction failure were identified in the combination therapy group.

In conclusion, according to our definition, 26 patients (12.1%) failed of remission induction (16 (20.8%) with GC monotherapy, and 10 (7.2%) with combination therapy comprising GC and IM). The lacrimal glands and lungs were the most common sites of remission induction failure. Eosinophilia, higher baseline RI, involvement of more than five organs and dacryoadenitis were risk factors for remission induction failure with GC monotherapy, and combination therapy of GC and IM should be considered for patients with more than three of these risk factors. After the remission-induction stage, patients who failed of remission induction had significantly higher ESR, CRP and IgG4.